Novel compound

ABSTRACT

Piperidine compounds, processes for preparing them, pharmaceutical compositions comprising them and their use in therapy are disclosed.

[0001] The present invention relates to a novel compound, to processesfor preparing it, pharmaceutical compositions comprising it and to itsuse in treating medical disorders.

[0002] Pharmaceutical products with antidepressant and anti-Parkinsonproperties are described in U.S. Pat. Nos. 3,912,743 and 4,007,196. Anespecially important compound among those disclosed is paroxetine, the(−)trans isomer of4-(4′-fluorophenyl)-3-(3′,4′-methylenedioxy-phenoxymethyl)-piperidine.This compound is used in therapy as the hydrochloride salt for thetreatment and prophylaxis of inter alia depression, obsessive compulsivedisorder (OCD) and panic.

[0003] We have now surprisingly discovered a novel salt of paroxetinewhich may be used as an alternative to the currently marketedhydrochloride, or as an intermediate in the preparation of thehydrochloride.

[0004] According to the present invention there is provided paroxetinemethanesulfonate as a novel compound.

[0005] In one aspect the novel salt of this invention is provided innon-crystalline form, which may be a solid or oil. The oil is preferablyabsorbed on a solid carrier, especially a carrier that is usable as acomponent of a pharmaceutical composition.

[0006] In another aspect the novel salt of this invention is provided incrystalline form. When the crystalline form exists as more than onepolymorph, each polymorph forms another aspect of this invention.

[0007] The paroxetine methanesulfonate salt may be obtained as asolvate; any such solvate forms a further aspect of this invention.

[0008] In a further aspect the present invention provides a process forthe preparation of a paroxetine methanesulfonate by precipitation from asolution of a paroxetine methanesulfonate, spray drying or freeze dryinga solution of a paroxetine methanesulfonate, evaporating a solution of aparoxetine methanesulfonate to a glass, or by vacuum drying of oils of aparoxetine methanesulfonate, or solidification of melts of a paroxetinemethanesulfonate.

[0009] Preferably such process provides crystalline paroxetinemethanesulfonate by crystallization or re-crystallization from asolution of a paroxetine methanesulfonate, and especially on acommercial scale in a reproducible manner.

[0010] Paroxetine methanesulfonate may be prepared by chemicalmodification of a precursor methanesulfonate salt. Suitable precursorsare those which may be converted to the methanesulfonate salt byhydrogenation. For example, the N-benzyl derivative of paroxetinemethanesulfonate in a suitable solvent (such as a C₁₋₄alkanol) may behydrogenated using a catalyst such as palladium on charcoal to generatea solution of paroxetine methanesulfonate.

[0011] Alternatively paroxetine methanesulfonate may be prepared bytreating paroxetine free base or a labile derivative thereof withmethanesulfonic acid or a labile derivative thereof. For exampleparoxetine methanesulfonate may be prepared by contacting stoichiometricamounts of the acid and paroxetine base, alternatively an excess of theacid may be used. Preferably the base is in solution and themethanesulfonic acid is used as a solid, liquid, or as a solution, forexample in water, ethers, or lower alcohols such as methanol, ethanol,and propan-2-ol, or a mixture of solvents. There is no need for a pureform of paroxetine base to be used as a starting material in thepreparation of the methanesulfonate salt.

[0012] The term ‘labile derivative thereof’ used herein with referenceto paroxetine refers to derivatives of paroxetine which under theconditions of the reaction with methanesulfonic acid or a labilederivative thereof form the paroxetine methanesulfonate salt. Suchlabile derivatives include without limitation a salt of paroxetine withan organic acid, particularly with acids weaker than methanesulfonicacid, or labile N-protected forms of paroxetine e.g. N-trimethyl silylor N-tert-butyloxycarbonyl. Examples of such salts of paroxetine,particularly with weaker acids are salts of paroxetine with organiccarboxylic acids, which may be saturated or unsaturated C₁₋₁₀ mono-,di-, or tri- carboxylic acids or hydroxy substituted such carboxylicacids, such as tartaric, and especially acetic acid, or maleic acid.Polymorphic forms of such salts, e.g. paroxetine maleate form A or B,may be used. Use of another salt of paroxetine as a starting material issuitable for preparation of the crystalline salt or, if a volatile acidsuch as acetic acid is used, non-crystalline salts by methods thatinvolve evaporation (such as freeze-drying and spray-drying).

[0013] With reference to methanesulfonic acid the term ‘labilederivative thereof’ refers to derivatives of methanesulfonic acid whichunder the conditions of reaction with paroxetine or a labile derivativethereof form paroxetine methanesulfonate salt. Such labile derivativesinclude without limitation salts thereof, especially a soluble salt,e.g. an ammonium or an amine salt thereof (e.g. ethylamine ordiethylamine), or immobilized amine salts e.g. a resin.

[0014] The paroxetine base may be provided as prepared according to theprocedures generally outlined in U.S. Pat. No. 4,007,196 andEP-B-0223403, the contents of which are included herein by way ofreference. An advantage of the present invention is that paroxetinesolutions prepared by a wide variety of synthetic routes may beincorporated into an efficient manufacturing process for paroxetinemethanesulfonate.

[0015] The paroxetine base may be provided in situ from a precedingreaction step in which the paroxetine base, or a labile derivativethereof, has been formed, e.g. present in the solvent medium in which ithas been so formed. Preceding reaction steps leading to the formation ofa solution of paroxetine or a labile derivative thereof are generallydeprotection reactions, part of a deprotection sequence, or a couplingreaction in the absence of a protecting group. Examples of suitableprotecting groups will be apparent to those skilled in the art andinclude without limitation: C₁₋₅ alkyl and C₁₋₅alkylaryl, allyl,phenacyl, quaternary ammonium; carbamates, such as methyl carbamate,diisopropylmethyl carbamate, 2,2,2-trichloroethyl carbamate, benzylcarbamate, (optionally substituted with, for example, C₁₋₅ alkyl, nitro,C₁₋₅ alkyloxy, halogen, cyano), vinyl carbamate, allyl carbamate;N-benzyl derivatives (optionally substituted with, for example, C₁₋₅alkyl, nitro, C₁₋₅ alkyloxy, halogen, cyano); amides, such as formyl,acetyl, acetoacetyl, benzoyl (optionally substituted with, for example,C₁₋₅ alkyl, nitro, C₁₋₅ alkyloxy, halogen, cyano); acetal derivatives,such as methoxymethyl, pivaloyloxymethyl; nitroso derivatives; silyl,such as trimethylsilyl, tert-butyldimethylsilyl, dimethylthexylsilyl;Sulfur acid derived groups, such as benzenesulfenyl, benzenesulfonyl(optionally substituted with, for example, C₁₋₅ alkyl, nitro, C₁₋₅alkyloxy, halogen, cyano).

[0016] An example of such a preceding step involves hydrolysis of acarbamate precursor (for example, the N-phenoxycarbonyl derivative ofparoxetine) in a suitable solvent (such as toluene) using a base such asan alkali metal hydroxide, and provides paroxetine base in solution, forexample in toluene. Alternatively the deprotection and salt conversionsteps may be combined in a one step process, for example by reactingdirectly an acid labile paroxetine precursor ( e.g. an acid-labilecarbamate such as the N-tertbutyloxycarbonyl derivative of paroxetine),with methanesulfonic acid in a suitable solvent (such as propan-2-ol,dichloromethane, dioxane or mixtures thereof). Another example is thatdisclosed in W098/01424, the contents of which are included herein byway of reference especially insofar as they relate to deprotection, inwhich hydrogenation in the presence of a catalyst such as platinum orpalladium e.g. deposited on carbon is used to remove a benzyl orsubstituted, e.g. C₁₋₅ alkyl or C₁₋₅ alkoxy substituted benzyl group.This reaction may for example take place in water, particularly underacid conditions, or in an organic solvent such as an alcohol, forexample a C₁₋₅ alkanol which may be straight or branched chain e.g.ethanol or 2-propanol, or a medium containing such an alcohol, and soprovides paroxetine or a labile derivative thereof in solution.

[0017] The paroxetine base or labile derivative thereof may be formed byevaporation of a solvent or solvent mixture in which the base or labilederivative is solubilized. Such a solvent or solvent mixture may forexample be a solvent or solvent mixture medium in which paroxetine hasbeen formed in situ e.g. in a preceding reaction step in the medium. Theparoxetine base may be produced in an organic solvent or mixture such asthose discussed herein, such as toluene or a medium containing toluene,which is then evaporated to leave a residue e.g. an oil, oily or solidor semi-solid residue. The unpurified paroxetine residue may be used inthe preparation of paroxetine methanesulfonate. Alternatively theresidue may be resolubilized in a suitable solvent such as a mediumcomprising an alcohol e.g. as discussed above, suitably propan-2-ol. Thesolvent may be heated and optionally agitated in order to effectcomplete dissolution of the residue.

[0018] In addition to the above-mentioned solvents, most commonly usedsolvents are suitable for mobilising, e.g. dissolving or suspending,paroxetine base, for example aromatic hydrocarbon type solvents such asalkylbenzenes e.g. toluene, xylene; alcohols such as C₁₋₈ alkanols whichmay be straight or branched chain e.g. methanol, ethanol, propan-2-ol;esters such as C₁₋₅ alkanoate esters such as ethyl acetate; ketones e.g.di- C₁₋₅ alkyl ketones such as acetone and butanone; amides such as C₁₋₅alkyl substituted acetamides e.g. dimethyl acetamide; heterocyclicamines e.g. pyridine; halogenated hydrocarbons such as fluoro and/orchloro C₁₋₁₀ alkanes e.g. dichloromethane; nitrites such as C₁₋₁₀ alkylnitrites e.g. acetonitrile, and ethers e.g. di- C₁₋₅ alkyl ethers andcyclic ethers such as tetrahydrofuran and diethyl ether.

[0019] In particular the following solvents are suitable for mobilisingparoxetine free base: toluene, alcohols such as methanol, ethanol,propan-2-ol, esters such as ethyl acetate, ketones such as acetone andbutanone, halogenated hydrocarbons such as dichloromethane, nitrites forexample acetonitrile, and ethers such as tetrahydrofuran and diethylether.

[0020] Suitably mixtures of solvents may also be used e.g. mixtures ofthe abovementioned solvents. The paroxetine base may be provided insolution in one solvent and then the solution diluted with anothersolvent, miscible with the first solvent. The second solvent may beadded to a solution of the paroxetine base or alternatively the solutionof paroxetine base in a first solvent may be added to the secondsolvent, in both cases optionally with stirring in the first solvent.The mixing of the paroxetine solution and a second solvent may occur atany convenient working temperature between e.g. −20° C. and the boilingpoint of the solvent, preferably between 15 to 80° C. under an inertatmosphere such as nitrogen.

[0021] Methanesulfonic acid is commercially available. It may be used asa neat liquid, or as a solution, for example in water, ethers, or loweralcohols such as methanol, ethanol and propan-2-ol, or a mixture ofsolvents. More generally it may be added as a neat liquid or preferablyin solution, for example in water, or a lower alcohol such as a C₁₋₅alkanol e.g. methanol, ethanol, or propan-2-ol; esters such as C₁₋₅alkanoate esters such as ethyl acetate; aromatic hydrocarbon solventse.g. a C₁₋₅ alkylbenzene such as toluene; di- C₁₋₅ alkyl ketone such asacetone, butanone, isomethylbutyl ketone, or a mixture of such solvents.The methanesulfonic acid may also be added in the form of labilederivatives as discussed above, such as a soluble salt, for exampleammonium methanesulfonate, or the methanesulfonic acid salt of an amine,for example a C₁₋₅ alkylamine such as ethylamine or diethylamine.

[0022] The concentration of paroxetine base or labile derivative thereofin the paroxetine feedstock is preferably in the range 5 to 80%weight/volume e.g. 5 to 50% weight/volume, more preferably in the range10 to 50%, particularly 10 to 30%. The concentration of methanesulfonicacid or labile derivative thereof in the acid feedstock, when added insolution, is preferably in the range 0.1 to 7 molar e.g. 0.1 to 3 molaror 0.5 to 1.5 molar, but more preferably between 1 and 5 molar. A highor low concentration of the acid may be added to a low or highconcentration, respectively, of the base, preferably a concentratedsolution of the acid is added to a dilute solution of the base.Suitably, depending on the solvent(s) used, the concentration ofparoxetine methanesulfonate formed may be in the range 2 to 50%weight/volume, typically 5 to 30%. The concentration ranges of thereactants as defined herein are found to facilitate formation insolution and subsequent precipitation of the paroxetine methanesulfonicacid salt in crystallized form.

[0023] The reaction of methanesulfonic acid with paroxetine base isexothermic and results in a rise in temperature; typically by between 10and 25° C., depending upon the concentration of the solution, unlesscontrolled by cooling. Suitably the addition, in either order, iscarried out above ambient conditions e.g. above 25° C. such as between30 and 80° C. preferably above 30° C. such as between 40 and 60° C. andpreferably under an inert atmosphere of nitrogen preferably withagitation e.g. stirring. Whilst temperatures above ambient suitably areused, so as to control the subsequent crystallization process and toproduce crystals having reproducible properties e.g. of uniform particlesize distribution and habit, temperatures in excess of 90° C. arepreferably avoided since degradation occurs resulting in coloration andoil formation. Optionally seeds may be added to the paroxetine solutionprior to the addition of the acid component.

[0024] The salt may be isolated in solid form by conventional means froma solution thereof obtained as above. For example, a non-crystallinesalt may be prepared by precipitation from solution, spray drying, andfreeze drying of solutions, evaporating a solution to a glass, or vacuumdrying of oils, or solidification of melts obtained from reaction of thefree base and the acid.

[0025] Prior to the isolation of the paroxetine methanesulfonate salt,water may be removed by azeotropic distillation to avoid the formationof hydrates or to obtain the product in anhydrous form. In that case,suitable solvents for the solution of the salt are those which form anazeotrope with water such as toluene and propan-2-ol. It should also beappreciated that mixtures of solvents can also be used to aid theazeotropic removal of water.

[0026] A crystalline salt may be prepared by various methods such asdirectly crystallizing the material from a solvent in which the producthas limited solubility or by triturating for example with ethers such asdiethyl ether or otherwise crystallizing a non-crystalline salt.

[0027] A number of solvents may be used for the crystallization processincluding those that are useful industrially; e.g. paroxetinemethanesulfonate may be crystallized from a relatively crude feedstocksuch as is commonly produced during the final stage of the chemicalsynthesis of paroxetine. In particular solvent systems which aresuitable for preparation of paroxetine methanesulfonates can also beused for recrystallization (including crystallization), for exampletoluene or lower alcohols followed by precipitation with ether orhexane. Alternatively, paroxetine methanesulfonate may be crystallizedor recrystallized by cooling and optionally seeding a hot solution in asuitable solvent such as propan-2-ol. An improved yield of the salt isobtained by evaporation of some or all of the solvent or bycrystallization at elevated temperature followed by controlled cooling,preferably in stages. Careful control of precipitation temperature andseeding may be used to improve the reproducibility of the productionprocess and the particle size distribution and form of the product.

[0028] One method for preparing crystalline paroxetine methanesulfonatesalt from solution comprises forming a supersaturated solution of thesalt in a solvent and allowing the crystalline salt to precipitate fromsolution, for example by maintaining the solution in relativelyquiescent conditions, e.g. under gentle stirring or leaving the solutionto stand. Seeding of the solution is optional. By selection of asuitable solvent medium and concentration the present invention providesa process in which crystalline paroxetine methanesulfonate precipitatesat temperatures above −20° C. e.g. above 0° C. e.g. around ambientconditions of 10 to 25° C. Suitable solvent media for this methodcomprise C₁₋₅ alkyl benzenes such as toluene, alcohols e.g. C₁₋₅alkanols such as 2-propanol, di- C₁₋₅ alkyl ketones such as acetone,ethers such as C₄₋₆ cyclic ethers such as tetrahydrofuran or mixturesthereof, and in particular mixtures of such alkyl benzenes with suchalkanols or ketones e.g. toluene and 2-propanol or toluene-acetonemixtures.

[0029] Another method of preparing crystalline paroxetinemethanesulfonate salt comprises forming a solution of the salt, forexample as defined herein, and subsequently supersatutarating thesolution for example by evaporation of the solvent and/or the additionof an anti-solvent to precipitate the crystalline salt from solution. An“anti-solvent”, as referred to herein, is a medium such as an organicliquid, which is miscible with a solvent for paroxetine methanesulfonatesalt but in which the paroxetine methanesulfonate salt is less solublethan in the solvent. Preferably the solubility of paroxetinemethanesulfonate salt in the anti-solvent is less than 1 mg/ml,preferably less than 0.2 mg/ml, especially less than 0.1 mg/ml. Examplesof anti-solvents include ethers, e.g. di- C₁₋₅ alkyl ethers and alkanes,such as C₅₋₁₀ alkanes which may be straight chain, branched chain orcyclic such as hexane. Solvent systems which are suitable forpreparation of paroxetine methanesulfonate, e.g. those discussed above,e.g. with reference to the solvent systems used for the deprotectionreactions discussed above, can also be used for recrystallization byprecipitation with an anti-solvent.

[0030] A preferred method of preparing crystalline paroxetinemethanesulfonate salt comprises cooling and optionally seeding asolution in a suitable solvent in which the paroxetine methanesulfonatesalt has a greater solubility at higher temperatures than at lowertemperatures so that as the solution cools the solubility at lowertemperatures will be exceeded and the paroxetine methanesulfonate saltcrystallises out.

[0031] Suitably the solubility of the paroxetine methanesulfonate saltat or immediately below the boiling point of the solvent is 5× or more,preferably 10× or more than that at ambient temperatures (e.g. ca. 20°C.) or lower. Suitable solvent systems include alkylbenzenes, e.g. C₁₋₃alkylbenzenes such as toluene, alcohols such as C₁₋₅ alkanols such asmethanol, ethanol, 2-propanol, and butan-1-ol, ketones such as di- C₁₋₅alkyl ketones such as acetone, methyl ethyl ketone, methylisobutylketone, esters such as C₁₋₅ alkyl C₁₋₅ alkanoates such as methylacetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, and ethers such as methyl t-butyl ether and C₄₋₆ cyclic etherssuch as tetrahydrofuran. Single and mixed solvent systems may be used asthe solvent or co-solvent of choice.

[0032] The starting temperature of the solution containing theparoxetine methanesulfonate salt to be crystallized may vary dependingupon the solubility of the reactants in the solvent system. Suitabletemperatures are between minus 20° C. and (+) 80° C., althoughtemperatures between (+)10° C. and (+)70° C. are preferred andtemperatures above (+)30° C. e.g. between (+)40° and (+)60° C. are mostpreferred. The solution is cooled to a temperature within the metastablezone in initiate crystallization. Once crystallization is underway, thetemperature of the mixture may be reduced steadily or in stages in orderto maintain a moderate degree of supersaturation and a controlledcrystallization at a high yield. The cooling rate is preferably withinthe range 0.1 to 5° C./minute and even more preferably is between 0.1 to2° C. per minute. The final temperature at the end of thecrystallization process is preferably around or below ambient e.g. 5 to25° C. even more preferably 10 to 20° C. Advantageously the methodsprovided herein do not require low temperatures i.e. less than 0° C. inorder to enable the crystallization process. An improved yield andquality of the paroxetine methanesulfonate salt may be obtained bycombining two or more of the aforementioned crystallization methods. Forexample by evaporating some or all the solvent and/or by crystallizationat elevated temperature followed by controlled cooling, preferably instages.

[0033] Seeds may be used to initiate, encourage or facilitatecrystallization. The seeds may comprise the methanesulfonate salt e.g.in a crude form such as that obtained by evaporation of a solution orother salt such that is substantially isomorphous with the paroxetinemethanesulfonate crystals formed. Preferably the seeds are produced froma standard manufacturing run and typically have a purity in the range 96to 99% or greater.

[0034] Inadvertent seeding may occur from the surrounding environmentresulting in poorly controlled crystallization. Preferablycrystallization is controlled by deliberate seeding at an above ambienttemperature and preferably from a solution that is not excessivelysupersaturated. Seeds may be added at any time before crystallizationbut preferably immediately before supersaturation of the paroxetinemethanesulfonate salt. Careful control of precipitation, temperature andseeding may be used to improve the reproducibility of the productionprocess and the particle size distribution and form of the product.

[0035] In further aspects the present invention provides for the use oftechniques such as insonation in the preparation of crystallineparoxetine methanesulfonate salt. Insonation and/or vigorous stirringmay be used to initiate nucleation for example in addition to the use ofanti-solvent(s), cooling, evaporation and/or seeding. Vigorous stirringis particularly useful when the crystallization vessel used has beenused previously in the manufacture of the methanesulfonate salt.

[0036] The methods provided herein provide crystalline paroxetinemethanesulfonate in a sufficiently pure state for its use as apharmaceutical per se or as a chemical intermediate in the preparationof other paroxetine forms. However the present invention also provides amethod for the optional additional purification of paroxetinemethanesulfonate by recrystallization. Such a method may also be used toprovide a solid state form having a particular desired habit andparticle size distribution.

[0037] The same solvents and methods for crystallization as hereindescribed can be used for recrystallization. The most commonly usedsolvents used for recrystallization are aromatic hydrocarbons e.g.toluene; alcohols such as C₁₋₈ alkanols which may be straight orbranched chain e.g. methanol, ethanol and propan-2-ol; esters such asC₁₋₅ alkanoate esters such as ethyl acetate; halogenated hydrocarbonssuch as fluoro and/or chloro C₁₋₁₀ alkanes e.g. dichloromethane andketones e.g. acetone and butanone. Mixtures of solvents may also be usede.g. mixtures containing water. A particularly useful solvent, both withrespect to its pharmaceutical acceptability and the quality of theresulting paroxetine methanesulfonate is propan-2-ol. Use of certainsolvents and/or solvent mixtures e.g. those containing propan-2-ol,avoids problems of oiling, i.e. formation of a soft sticky product. Inaddition difficulties in stirring and adhesion of product to thecontainer walls as well as problems associated with drying the productare avoided. Typically between 2 and 20 l/kg of solvent may be used forrecrystallization on an industrial scale, preferably between 3 and 10l/kg.

[0038] The abovementioned processes for preparing the paroxetinemethanesulfonate salt may be carried out in various types of reactionvessels. The crystallisation of paroxetine methanesulfonate saltsuitable for use as a pharmaceutical may be carried out in a vessel suchas a stirred tank reactor, which may be constructed from glass-lined orstainless steel, fitted with baffles and one or more jackets to controlthe temperature profile during crystallisation. Alternatively, thecrystallisation may be carried out in a specially designed batchcrystalliser, in which fine control of the crystallisation conditionscan be maintained. Suitable batch crystallisers include draft tubebaffled (DTB) crystallisers, double propeller (DP) crystallisers andfluidised bed crystallisers (Oslo cooling crystallisers). Variouscontinuous crystallisers, such as draft tube cooling, direct contactcooling, scraped surface and turbulence crystallisers may also beemployed.

[0039] Suitably crystallization is carried out in a vessel provided withone or more high intensity ultrasonic horns, for example with titaniumalloy resonant horns which enable acoustic energy to be coupled to thecrystallizing medium at a frequency of 20 kHz and an amplitude of 12microns or more, and with a device that modifies the power outputaccording to the acoustic parameters of the load. Insonation may beintermittent, limited to part of the apparatus, or discontinued oncesufficient nuclei have been generated.

[0040] The solvent wet cake, comprising paroxetine methanesulfonate,recovered from the crystallization and recrystallization processesdescribed herein may be dried so as to give the desired moisture contentfor the salt form. Drying may be effected by using one or more dryerse.g. a conventional drying oven, a filter dryer or a stirred pan dryer.Suitably the drying temperature may vary from below ambient to 80° C.and a typical drying cycle may take 12-24 hours. Alternative dryingmethods, e.g. using a microwave oven, may also be used. Advantageouslysuch a method enables more accurate temperature control and drying timesmay be reduced considerably e.g. a typical drying cycle may take2-6hours, depending upon the quantity of material to be dried and themicrowave power used.

[0041] In a further aspect the present invention provides the paroxetinemethanesulfonate salt in a crystalline form having an X-ray powderdiffraction pattern identical or substantially identical to that listedunder Example 2 or Example 3 below. Suitably the crystalline paroxetinemethanesulfonate has inter alia one or more of the followingcharacteristic XRD peaks: 8.3, 10.5, 15.6, 16.3, 17.7, 18.2, 19.8, 20.4,21.5, 22.0, 22.4, 23.8, 24.4, 25.0, 25.3, 25.8, 26.6, 30.0, 30.2, and31.6±0.2 degrees 2 theta.

[0042] In a further aspect the present invention provides the paroxetinemethanesulfonate salt in a crystalline form having an infra-red spectrumidentical or substantially identical to that listed under Example 2 orExample 3 below. Suitably the crystalline paroxetine methanesulfonatehas inter alia one or more of the following characteristic IR peaks:1603, 1513, 1194, 1045, 946, 830, 776, 601, 554, and 539±4 cm−1.

[0043] Crystals of the present invention may have a range of particlesizes. Typically the particle size is distributed over a range. Suitablymore than 90% of the particles have a size of 1 to 1000 microns andpreferably are within the range 50 to 300 microns, as measured by LowAngle Laser Light Scattering (LALLS) using a Sympatec Helos/Rodosinstrument.

[0044] Typically methanesulfonate salts produced in the presentinvention have a melting point greater than 143° C., e.g. having amelting point of 143 to 146° C., preferably within the range from 144 to148° C., more preferably greater than 144° C., e.g. 145 to 146° C., 147to 148° C., or 146 to 148° C.

[0045] The paroxetine methanesulfonate salt may be obtained as asolvate, when during isolation from solution it becomes associated withthe solvent in which it is dissolved. Any such solvate forms a furtheraspect of this invention e.g. crystallization of paroxetinemethanesulfonate from acetonitrile results in the formation of a 1:1solvate.

[0046] Solvates may be returned to the unsolvated paroxetinemethanesulfonate salt by heating, for example by oven-drying, or bytreatment with a displacement solvent which does not form a solvate.

[0047] Individual polymorphs are preferably crystallized directly from asolution of the paroxetine methanesulfonate salt, althoughrecrystallizing a solution of one polymorph using seeds of anotherpolymorph may also be carried out.

[0048] The compounds of this invention may be used to treat and preventthe following disorders:

[0049] Alcoholism

[0050] Depression

[0051] Panic Disorder

[0052] Obesity

[0053] Migraine

[0054] Anorexia

[0055] Pre-Menstrual Syndrome (PMS)

[0056] Trichotillomania

[0057] Substance Abuse

[0058] Anxiety

[0059] Obsessive Compulsive Disorder

[0060] Chronic Pain

[0061] Senile Dementia

[0062] Bulimia

[0063] Social Phobia

[0064] Adolescent Depression

[0065] Dysthymia

[0066] These disorders are herein after referred to as “the Disorders”.

[0067] The present invention further provides a method for treatingand/or preventing any one or more of the Disorders by administering aneffective and/or prophylactic amount of a salt of the invention to asufferer in need thereof.

[0068] The present invention further provides a pharmaceuticalcomposition for use in the treatment and/or prevention of the Disorderswhich comprises an admixture of a salt of the invention with apharmaceutically acceptable carrier.

[0069] The present invention also provides the use of a salt of theinvention for treating and/or preventing the Disorders.

[0070] The present invention also provides the use of a salt of theinvention in the manufacture of a medicament for treating and/orpreventing the Disorders.

[0071] Most suitably the present invention is applied to the treatmentof depression, OCD and panic.

[0072] The compositions of this invention are usually adapted for oraladministration, but formulations for dissolution for parentaladministration are also within the scope of this invention.

[0073] The composition is usually presented as a unit dose compositioncontaining from 1 to 200 mg of active ingredient calculated on a freebase basis, more usually from 5 to 100 mg, for example 10 to 50 mg suchas 10, 12.5, 15, 20, 25, 30 or 40 mg by a human patient. Most preferablyunit doses contain 20 mg of active ingredient calculated on a free basebasis. Such a composition is normally taken from 1 to 6 times daily, forexample 2, 3 or 4 times daily so that the total amount of active agentadministered is within the range 5 to 400 mg of active ingredientcalculated on a free base basis. Thus a suitable daily dose is from 0.05to 6 mg/kg, more preferably 0.14 to 0.86 mg/kg. Most preferably the unitdose is taken once a day.

[0074] Preferred unit dosage forms include tablets or capsules,especially a modified oval or pentagonal shaped tablet.

[0075] The compositions of this invention may be formulated byconventional methods of admixture such as blending, filling andcompressing.

[0076] Suitable carriers for use in this invention include a diluent, abinder, a disintegrant, a coloring agent, a flavouring agent and/orpreservative. These agents may be utilized in conventional manner, forexample in a manner similar to that already used for marketedanti-depressant agents.

[0077] Suitably the carrier for use in this invention comprises adisintegrant.

[0078] Such disintegrant will be present in an effective amount, forexample up to 30% by weight of the composition, to ensure disintegrationof the composition in vivo.

[0079] Suitably the carrier for use in this invention comprises abinder.

[0080] Suitably the carrier for use in this invention comprises acoloring agent.

[0081] Such coloring agent may be used to color a tablet coating.Commonly used coloring agents are ‘lakes’ which are largely waterinsoluble forms of synthetic water soluble dyes. They are prepared byadsorbing a sodium or potassium salt of a dye onto a very fine substrateof hydrated alumina, followed by treatment with a further solublealuminium salt. The lake is then purified and dried. Examples ofsuitable lakes include yellow colored lakes such as sunset yellow andquinoline yellow; red colored lakes e.g. helindone pink; blue coloredlakes e.g. indigotine; or mixtures thereof. Suitably compositions of thepresent invention comprise an amount of coloring agent sufficient tocolor the dosage form e.g. 0.001-1.0% w/w.

[0082] Suitably the carrier for use in this invention comprises aflavouring agent.

[0083] Suitably the carrier for use in this invention comprises apreservative.

[0084] Specific examples of pharmaceutical compositions include thosedescribed EP-B-0223403, and U.S. Pat. No. 4,007,196 in which theproducts of the present invention may be used as the active ingredients.

[0085] In a further aspect the present invention provides a packcomprising a pharmaceutical composition of the present invention.

[0086] This invention provides the use of paroxetine methanesulfonate asan intermediate in the preparation of the hydrochloride and alsoprovides a process which comprises converting paroxetinemethanesulfonate into paroxetine hydrochloride.

[0087] The following Examples illustrate the present invention. Allmelting points quoted were determined using conventional melting pointapparatus such as a Bushi apparatus, and were computed from a calibratedinstrument.

EXAMPLE 1

[0088] A solution of paroxetine base in toluene (2.1 g in 5 ml) wasmixed with a solution of methanesulfonic acid (0.61 g) in toluene (15ml), and stirred at 50° C. for 20 minutes. The solvent was removed invacuo, and the residue triturated with diethyl ether (50 ml) to producea crystalline solid, which was filtered, washed with diethyl ether (15ml) and dried in a vacuum desiccator.

[0089] Yield 2.62 g.

EXAMPLE 2

[0090] A solution of paroxetine base in toluene (42 g in 100 ml) wasadded to a solution of methanesulfonic acid (12.2 g) in toluene (300ml). The solution was stirred for 30 minutes at 50° C., then the solventwas removed by evaporation at reduced pressure. The residue wastriturated with diethyl ether (300 ml), and stirred at approximately 20°C. to produce a white crystalline solid which was filtered, washed withdiethyl ether (2×100 ml) and dried in a vacuum desiccator.

[0091] Yield 54.55 g. m. p. 143×146° C.

[0092] IR nujol mull:

[0093] Bands at inter alia 1603, 1513, 1462, 1377, 1194, 1045, 946, 830,776, 601, 554, 539 cm⁻¹.

[0094] The same characterising IR bands are found when using KBr discsexcept for the 1462 and 1377 bands which are characteristic of nujol.

[0095] X-ray powder diffractogram major peaks (CuK_(2a)): Angle [⁰2θ]Rel.Int [%] 8.3 38.5 10.5 11.3 15.6 10.9 16.3 13.8 17.7 43.6 18.2 92.819.8 11.4 20.4 23.4 21.5 50.2 22.0 70.4 22.4 10.7 23.8 22.4 24.4 100.025.0 27.8 25.3 17.1 25.8 25.2 26.6 22.5 30.0 11.1 30.2 13.6 31.6 10.7

EXAMPLE 3

[0096] A mixture of methanesulfonic acid (13.7 g) dissolved in toluene(400 ml) and a solution of paroxetine base (47.0 g) in toluene (100 ml),obtained directly from the base hydrolysis of the N-phenoxycarbonylintermediate, was evaporated at reduced pressure at 18° C. The resultingwhite, non-crystalline solid was triturated with diethyl ether to giveparoxetine methanesulfonate as a white crystalline solid. The productwas collected by filtration and dried overnight in a vacuum desiccatorover phosphoric oxide. Yield=56.8 g. Proton nuclear magnetic resonancespectroscopy showed that the molar ratio of paroxetine tomethanesulfonic acid was 1:1.

[0097] IR (nujol mull): Bands at, inter alia, 1638, 1614, 1603, 1513,1499, 1399, 1377, 1278, 1254, 1194, 1163, 1145, 1132, 1103, 1095, 1046,1034, 1010, 946, 927, 916, 870, 845, 830, 822, 787, 776, 766, 721, 601,572, 554, 539, 529, 514 cm⁻¹.

[0098] IR (attenuated total reflection): Bands at, inter alia, 1637,1614, 1603, 1512, 1498, 1469, 1399, 1277, 1254, 1192, 1163, 1145, 1132,1094, 1076, 1045, 1032, 946, 926, 916, 870, 845, 829, 822, 809, 787,775, 766, 721, 600, 572, 554 cm⁻¹.

[0099] X-ray diffractogram major peaks (Cu K_(2α)): Angle [⁰2θ] Rel. Int[%] 6.7 8.5 8.2 46.5 10.4 9.9 10.9 5.5 13.9 8.6 14.7 7.1 15.6 8.2 16.315.8 17.7 39.6 18.2 93.9 19.8 9.0 20.5 23.0 21.5 50.2 21.9 83.7 22.411.8 23.8 23.0 24.3 100.0 24.9 29.4 25.3 17.5 25.7 26.0 26.5 21.9 27.35.3 27.8 11.1 28.3 5.9 28.6 7.6 29.0 8.0 29.6 8.6 30.0 12.5 30.2 14.430.6 10.2 31.5 13.7 32.4 7.5 33.1 10.8 34.5 7.1 34.4 6.5

EXAMPLE 4

[0100] A round bottomed flask was charged with a solution of paroxetinebase (23.5 g) in toluene (50 ml), obtained directly from the basehydrolysis of the N-phenoxycarbonyl intermediate, and the toluene wasremoved by evaporation at reduced pressure. The residue was dissolved inpropan-2-ol (150 ml) with gentle warming, and the solution cooled to 18°C. Methanesulfonic acid (6.86 g) was added, and the solution stirred at18° C. Seeds of crystalline paroxetine methanesulfonate were added, andthe mixture was ultrasonicated. After about 1 minute, a densecrystalline precipitate formed, which was allowed to stand for 20minutes. The product, paroxetine methanesulfonate, was collected byfiltration and dried over phosphoric oxide in a vacuum desiccator.

[0101] Yield 29.8 g Melting point=145-146° C.

[0102] The infra-red spectrum and X-ray powder diffractogram were thesame as in Example 3.

[0103] IR (KBr disc): Bands at, inter alia, 3006, 1638, 1614, 1604,1513, 1499, 1469, 1422, 1399, 1358, 1336, 1278, 1194, 1163, 1144, 1132,1095, 1091, 1045, 1034, 946, 927, 916, 870, 830, 822, 787, 776, 766,601, 572, 554, 539, 529, 514 cm−1.

EXAMPLE 5

[0104] A solution of paroxetine base (4.7 g) in toluene (40 ml),obtained directly from the base hydrolysis of the N-phenoxycarbonylintermediate, was stirred at 18° C. and methanesulfonic acid (0.93 ml)was added dropwise. Seeds of crystalline paroxetine methanesulfonatewere added and the mixture was treated with ultrasound. After a shorttime, crystalline paroxetine methanesulfonate precipitated fromsolution, and the mixture was left to stand overnight. The product wascollected by filtration and dried under vacuum.

EXAMPLE 6

[0105] Unpurified paroxetine base (4.7 g) was dissolved intetrahydrofuran (10 ml) with gentle warming. Methanesulfonic acid (1.37g) was added dropwise to the stirred solution and the clear mixturecooled to 18° C. After five minutes, seeds of crystalline paroxetinemethanesulfonate were added, and the mixture was insonated. Crystallineparoxetine methanesulfonate precipitated from solution, and the mixturewas left to stand overnight. The product was collected by filtration anddried under vacuum.

EXAMPLE 7

[0106] Unpurified paroxetine base (4.7 g) was dissolved in butanone (50ml), and methanesulfonic acid (1.37 g) was added dropwise. Seeds ofcrystalline paroxetine methanesulfonate were added to the stirredsolution, and the clear mixture was insonated. After a short while,crystalline paroxetine methanesulfonate precipitated from solution, andthe mixture was left to stand overnight. The product was collected byfiltration and dried under vacuum.

EXAMPLE 8

[0107] Propan-2-ol (40 ml) was added at 19° C. under a nitrogenatmosphere to a stirred solution of paroxetine base (8.0 g) in toluene(20 ml), obtained directly from the base hydrolysis of theN-phenoxycarbonyl intermediate. Methanesulfonic acid (2.45 g) was addedto the solution and stirring was continued for one hour. A whitecrystalline solid formed and was collected by filtration, washed withpropan-2-ol (15 ml) and dried at 40° C. under vacuum for one hour toproduce crystalline paroxetine methanesulfonate, 8.8 g (85%).

[0108] IR (nujol mull): bands at inter alia 1638, 1603, 1513, 1377,1278, 1194, 1093, 1045, 1033, 946, 927, 830, 786, 776, 722, 601, 554,540 cm⁻¹

EXAMPLE 9

[0109] Acetone (40 ml) was added at 19° C. under a nitrogen atmosphereto a stirred solution of paroxetine base (8.0 g) in toluene (20 ml),obtained directly from the base hydrolysis of the N-phenoxycarbonylintermediate. Methanesulfonic acid (2.45 g) was added to the solutionand stirring was continued for one hour. The white crystalline solidwhich separated from the solution was collected by filtration, washedwith acetone (15 ml) and dried at 40° C. under vacuum for one hour toproduce crystalline paroxetine methanesulfonate, 9.7 g (94%).

[0110] IR (nujol mull): bands at inter alia 1638, 1603, 1513, 1377,1278, 1194, 1093, 1046, 1033, 946, 927, 830, 786, 776, 722, 601, 554,540 cm⁻¹

EXAMPLE 10

[0111] Methanesulfonic acid (2.45 g) was added at 19° C. under anitrogen atmosphere to a solution of paroxetine base (8.0 g) in toluene(50 ml), obtained directly from the base hydrolysis of theN-phenoxycarbonyl intermediate, and the mixture was stirred for onehour. A white crystalline solid separated from the solution and wascollected by filtration, washed with toluene (10 ml) and dried at 40° C.under vacuum for one hour to produce paroxetine methanesulfonate, 9.6 g(93%).

[0112] IR (nujol mull): bands at inter alia 1638, 1603, 1513, 1377,1278, 1194, 1094, 1046, 1033, 946, 927, 830, 786, 776, 722, 601, 554,540 cm⁻¹

EXAMPLE 11

[0113] A stirred mixture of N-phenoxycarbonyl paroxetine (19.4 g),potassium hydroxide (17.5 g) and toluene (300 ml) was heated to refluxunder a nitrogen atmosphere for 3 hours. The mixture was cooled to roomtemperature, washed with water (200 ml) and the organic layer separated,dried over magnesium sulphate and concentrated to a total volume ofapproximately 80 ml. Methanesulfonic acid (4.35 g) was added to thesolution and the mixture stirred for one hour. The white crystallinesolid which crystallised during this time was collected by filtration,washed with toluene (20 ml) and dried at 40° C. under vacuum for onehour to produce paroxetine methanesulfonate, 16.7 g (91%).

[0114] IR (nujol mull): bands at inter alia 1638, 1603, 1513, 1377,1278, 1194, 1094, 1046, 1033, 946, 927, 830, 786, 776, 722, 601, 554,540 cm⁻¹

EXAMPLE 12

[0115] A round bottomed flask was charged with a solution of paroxetinebase (23.5 g) in toluene (50 ml), obtained directly from the basehydrolysis of the N-phenoxycarbonyl intermediate. The toluene wasremoved in vacuo to produce an oily residue. To this residue was addedpropan-2-ol (50 ml) and the mixture was warmed to ensure totaldissolution of the paroxetine. The temperature of the solution wascooled to 18° C. and methanesulfonic acid (6.86 g) was added, then thesolvents were removed at reduced pressure and replaced with freshpropan-2-ol-110 ml). The solution was heated to reflux temperature,cooled to 18° C., and seeded with crystalline paroxetinemethanesulfonate. Crystallisation was induced with vigorous stirring andinsonation, and the product collected by filtration, and dried overphosphorus pentoxide in a vacuum desiccator to produce paroxetinemethanesulfonate as a white crystalline solid.

[0116] Melting point=145-146° C.

[0117] The infra-red spectrum and X-ray powder diffractogram were thesame as in Example 3.

EXAMPLE 13

[0118] Paroxetine methanesulfonate (0.7 g) was added to ethanol (2 ml),stirred and heated to reflux temperature to dissolve. The resultingsolution was cooled to 18° C. and seeded with crystals of paroxetinemethanesulfonate. A white precipitate of needle crystals formed, whichwas collected by filtration, washed with ethanol and dried in vacuo overphosphorous pentoxide to produce crystalline paroxetinemethanesulfonate.

[0119] Yield=0.52 g. Melting point: 146-147° C.

EXAMPLE 14

[0120] Paroxetine methanesulfonate (0.95 g) was added to acetone (10 ml)and the solution heated to reflux temperature while stirring. Thesolution was cooled to 18° C. and seeded with crystals of paroxetinemethanesulfonate. A white precipitate of needle crystals formed, and wascollected by filtration, washed with acetone and dried in vacuo overphosphorous pentoxide to produce crystalline paroxetinemethanesulfonate. Yield=0.71 g

[0121] Melting point: 146-148° C.

[0122] The infra-red spectrum and X-ray powder diffractogram were thesame as in Example 3.

EXAMPLE 15

[0123] Paroxetine methanesulfonate (1.06 g) was added to ethyl acetate(70 ml) and the solution was heated to reflux temperature whilestirring. The solution was cooled to 18° C. and seeded with crystals ofparoxetine methanesulfonate. A white precipitate of large needlecrystals (0.4-1 mm in length) formed, and was collected by filtration,washed with ethyl acetate and dried in a vacuum desiccator overphosphorous pentoxide to produce crystalline paroxetinemethanesulfonate. Yield=0.92 g

[0124] Melting point: 146-147° C.

[0125] The infra-red spectrum and X-ray powder diffractogram were thesame as in Example 3.

EXAMPLE 16

[0126] Paroxetine methanesulfonate (1.11 g) was added to toluene (4 ml)and the solution was heated to reflux temperature while stirring. Theresulting solution was cooled to 18° C. and seeded with crystals ofparoxetine methanesulfonate. A white precipitate of needle crystalsformed, which was collected by filtration, washed with toluene and driedin a vacuum desiccator over phosphorous pentoxide to produce crystallineparoxetine methanesulfonate.

[0127] The infra-red spectrum and X-ray powder diffractogram were thesame as in Example 3.

EXAMPLE 17

[0128] A toluene solution (1.0 L) containing unpurified paroxetine base(approximately 225 g) was charged to a nitrogen purged reactor andstirred at 20° C. The vessel was seeded with paroxetinemethanesulfonate, then a solution of methane sulfonic acid (70 g) inpropan-2-ol (0.4 L) was added slowly over a period of 50 minutes.Paroxetine methansulfonate was precipitated as a white crystalline solidduring the addition, and the temperature at the end of the addition was29.6° C. The suspension was stirred for a further 1 hour, during whichtime the temperature was reduced to 22° C. The product was collected byfiltration, washed on the filter with propan-2-ol (2×0.4 L) and dried ina vacuum oven at 40° C. for 24 hours. Yield 230 g

EXAMPLE 18

[0129] Paroxetine methanesulfonate (0.81 g) was added to methyl ethylketone (10 ml) and the mixture was heated to reflux temperature whilestirring to dissolve, then cooled to 18° C. A white precipitate ofneedle crystals formed, which was collected by filtration, washed withmethyl ethyl ketone and dried in a vacuum desiccator over phosphorouspentoxide to produce crystalline paroxetine methanesulfonate.

[0130] The infra-red spectrum and X-ray powder diffractogram were thesame as in Example 3.

EXAMPLE 19

[0131] Paroxetine methanesulfonate (1.06 g) was added to butan-1-ol (2ml) and the mixture was heated to reflux temperature while stirring todissolve, then cooled to 18° C. A white precipitate of needle crystalsformed, which was collected by filtration, washed with acetone and driedin vacuo over phosphorous pentoxide to produce crystalline paroxetinemethanesulfonate.

[0132] The infra-red spectrum and X-ray powder diffractogram were thesame as in Example 3.

EXAMPLE 20

[0133] Paroxetine methanesulfonate (1.05 g) was added to tetrahydrofuran(9 ml) and the mixture was heated to reflux temperature while stirringto dissolve, then cooled to 18° C. A white precipitate of needlecrystals formed, which was collected by filtration, washed withtetrahydrofuran and dried in a vacuum desiccator over phosphorouspentoxide to produce crystalline paroxetine methanesulfonate.

[0134] The infra-red spectrum and X-ray powder diffractogram were thesame as in Example 3.

EXAMPLE 21

[0135] A mixture of paroxetine methanesulfonate (5.0 g) and propan-2-ol(30 ml) was stirred and heated to 70° C. to produce a clear solution.The solution was then cooled at a rate of 2° C. per minute to 55° C. andthen seeded with crystals of paroxetine methanesulfonate. The mixturewas held at this temperature for 10 minutes and then cooled to 20° C.over a period of 35 minutes. The crystalline solid was collected byfiltration, washed with propan-2-ol (10 ml) and dried at 40° C. undervacuum for 2 hours to produce paroxetine methanesulfonate, 4.5 g.

EXAMPLE 22

[0136] A mixture of paroxetine methanesulfonate (5.0 g), toluene (55 ml)and acetone (30 ml) was stirred and heated to 75° C. to produce a clearsolution. The solution was then cooled to 45° C. over a period of 15minutes at which point seed crystals of paroxetine methanesulfonate wereadded. The stirred mixture was held at 45° C. for 10 minutes and wasthen cooled to 20° C. over a period of 25 minutes. The crystalline solidwas collected by filtration, washed with acetone (20 ml) and dried at40° C. under vacuum for 2 hours to produce paroxetine methanesulfonate,4.2 g.

EXAMPLE 23

[0137] A mixture of paroxetine methanesulfonate (5.0 g) and toluene (30ml) was stirred and heated to 90° C. to produce a clear solution. Thesolution was then cooled to 45° C. over a period of 25 minutes. At thispoint the solution became cloudy and crystallization proceeded rapidlyto produce a thick suspension. The cream colored crystalline solid wascollected by filtration, washed with toluene (10 ml) and dried at 40° C.under vacuum for 2 hours to produce paroxetine methanesulfonate, 4.7 g.

EXAMPLE 24

[0138] A mixture of paroxetine methanesulfonate (5.0 g), propan-2-ol (30ml) and water (1 ml) was stirred and heated to reflux to produce a clearsolution. The mixture was cooled to 40° C. and was seeded with crystalsof paroxetine methanesulfonate. The stirred mixture was then cooled to21° C. over a period of 40 minutes to produce a thick suspension. Theproduct was collected by filtration, washed with propan-2-ol (10 ml) anddried at 40° C. under vacuum for 2 hours to produce paroxetinemethanesulfonate (3.8 g) as a white crystalline solid.

EXAMPLE 25

[0139] A solution of paroxetine free base (81.0 g) in toluene (500 ml)was prepared by treating a solution of N-phenoxycarbonyl paroxetine intoluene with potassium hydroxide, followed by washing with water,separation, drying over magnesium sulphate and concentration of theorganic layer. Methanesulfonic acid (25.0 g) was added to the stirredsolution, under a nitrogen atmosphere, at an initial temperature of 21°C. and the mixture was allowed to rise to 45° C. The mixture was cooledto 21° C. over a period of 30 minutes and stirring continued for afurther 30 minutes. The cream colored crystalline solid was collected byfiltration, washed with toluene and dried at 40° C. under vacuum for 1hour to produce paroxetine methanesulfonate, 104.5 g.

[0140] A 90 g portion of this material was recrystallized frompropan-2-ol using a computer controlled automated reactor systemaccording to the following procedure:

[0141] Paroxetine methanesulfonate (90 g) and propan-2-ol (500 ml) werecharged to a computer controlled 1-liter reactor equipped with athermostatic jacket, an internal temperature probe and an overhead motordriven agitator. The reactor was programmed to use the externalthermostatic jacket to enable specific control of the internal reactiontemperature over a given period of time. The mixture was stirred at arate of 100 rpm and heated to 70° C. over a period of 50 minutes andmaintained at that temperature for 10 minutes to produce a clearsolution. The solution was then stirred and cooled at a rate of 1° C.per minute for 25 minutes at which point seed crystals were added. Thestirred mixture was then cooled at a rate of 1° C. per minute for afurther 25 minutes. The resulting suspension was drained from thereactor and the solid isolated by vacuum filtration. The filter cake waswashed with propan-2-ol (100 ml) and the product dried at 40° C. undervacuum for 2 hours to produce paroxetine methanesulfonate as a whitecrystalline solid, 82.8 g.

EXAMPLE 26

[0142] Paroxetine methanesulfonate (2.47 g) was dissolved inacetonitrile (10 ml), and the solution was brought to reflux temperaturewith vigorous stirring. The solution was subsequently cooled to −78° C.After a short period crystallisation occurred at the bottom of theflask. After a further half-hour, the product was collected byfiltration and dried in a vacuum desiccator over phosphorous pentoxide.The following data indicated that the product formed was crystallineparoxetine methanesulfonate acetonitrile solvate.

[0143] Yield=2.58 g

[0144] Molar ratio of paroxetine to methanesulfonic acid=1:1

[0145] Acetonitrile content (estimated by NMR) 8.5% wt/wt.

[0146] IR (attenuated total reflectance):

[0147] Bands at inter alia 2550, 1624, 1606, 1512, 1488, 1471, 1418,1377, 1335, 1270, 1207, 1180, 1159, 1141, 1098, 1076, 1039, 1028, 1011,987, 968, 951, 922, 867, 844, 774, 719, 670, 613, 579 cm⁻¹.

[0148] IR (nujol mull):

[0149] Bands at inter alia 2549, 2247, 1623, 1514, 1489, 1470, 1418,1377, 1336, 1270, 1209, 1182, 1162, 1098, 1042, 1028, 1012, 987, 922,845, 832, 813, 792, 776, 720, 671, 614, 580, 552, 537, 524 cm⁻¹.

[0150] X-ray powder diffractogram major peaks (Cu K_(2α)): Angle [⁰2θ]Rel. Int [%] 6.4 5.0 7.8 0.6 9.6 9.2 12.1 1.2 13.0 45.8 14.5 5.1 14.810.7 15.9 8.9 17.4 5.3 18.1 3.6 19.6 81.1 20.2 13.0 20.9 100.0 21.9 11.323.2 19.3 24.0 28.9 24.4 5.5 25.2 12.5 26.2 13.6 27.0 15.2 27.2 16.928.1 3.5 29.4 3.2 30.0 8.9 30.5 30.8 31.7 9.4 32.2 4.7 32.9 15.1 33.83.2 34.2 4.8

EXAMPLE 27

[0151] Paroxetine methanesulfonate (6.37 g) was dissolved inacetonitrile (70 ml), and the solution was brought to reflux temperaturewith vigorous stirring. The solution was subsequently cooled to 45° C.After 1 hour the clear solution was seeded with paroxetinemethanesulfonate seeds obtained in Example 26, and treated withultrasound. During insonation, rapid crystallisation took place. Theresulting precipitate was further diluted with acetonitrile (100 ml) andafter a further half hour of standing at 45° C., paroxetinemethanesulfonate acetonitrile solvate was collected by filtration,washed with acetonitrile and dried in a vacuum desiccator overphosphorous pentoxide.

[0152] Yield 7.3 g

[0153] IR and X-ray powder diffraction patterns similar to thoseobtained in Example 26.

[0154] Molar ratio of paroxetine to methanesulfonic acid=1:1

[0155] Acetonitrile content (estimated by NMR) 7.9% wt/wt.

[0156] A small sample was placed in a vacuum desiccator over a period of24 hours. NMR analysis of the resulting product indicated the presenceof 6.4% acetonitrile.

[0157] DSC (open pan): rate of heating 10.0° C./min, paroxetinemethanesulfonate acetonitrile solvate 2.036 mg.

[0158] endotherm peak maximum at 77.8° C.

[0159] exotherm peak maximum at 85.0° C.

[0160] endotherm peak maximum at 92.8° C.

[0161] endotherm peak maximum at 148.5° C.

[0162] DSC (closed pan): rate of heating 10.0° C./min, paroxetinemethanesulfonate

[0163] acetonitrile solvate 2.315 mg.

[0164] endotherm peak maximum at 68.0° C.

[0165] exotherm peak maximum at 85° C.

[0166] endotherm peak maximum at 92.1° C.

[0167] endotherm peak maximum at 134.7° C.

[0168] endotherm peak maximum at 148.8° C.

EXAMPLE 28

[0169] Paroxetine methanesulfonate (2.22 g) was dissolved inacetonitrile (25 ml) and the solution was brought to reflux temperaturewith stirring. The solution was subsequently cooled to 45° C. and seededwith paroxetine methanesulfonate seeds obtained in Example 26. After 2hours the solution was cooled to 18° C. and after a further short periodthe clear solution began to crystallise. Paroxetine methanesulfonateacetonitrile solvate was collected by filtration in an inert atmosphere,washed with acetonitrile and dried in a vacuum desiccator overphosphorous pentoxide.

[0170] Yield=2.6 g

[0171] Molar ratio of paroxetine to methanesulfonic acid =1:1

[0172] Acetonitrile content (estimated by NMR) 7.4% wt/wt.

[0173] IR and X-ray powder diffraction patterns similar to thoseobtained in example 26.

EXAMPLE 29

[0174] A round-bottomed flask was charged with a solution of paroxetinebase (10.37 g) in toluene (24 ml). The toluene was removed at reducedpressure to produce an oily residue. The residue was diluted withacetonitrile (150 ml) and the solution was heated to reflux temperature.Seed crystals of paroxetine methanesulfonate acetonitrile solvate wereadded, followed by the dropwise addition of methanesulfonic acid (2.1ml). The temperature of the solution was cooled to 45° C. and themixtures insonated for 5 minutes. Crystallisation occurred and thecontents of the flask were further diluted with acetonitrile (100 ml).Paroxetine methanesulfonate acetonitrile solvate was collected byfiltration under an argon atmosphere, washed with acetonitrile and driedin a vacuum desiccator containing phosphorus pentoxide to produce awhite crystalline solid.

[0175] Yield 11.3 g

[0176] Molar ratio of paroxetine to methanesulfonic acid =1:1

[0177] Acetonitrile content (estimated by NMR) 10.2% wt/wt.

[0178] A small sample was placed in a vacuum desiccator over a period of24 hours. NMR analysis of the resulting product indicated the presenceof 8.0% acetonitrile.

EXAMPLE 30

[0179] Paroxetine methanesulfonate (3.61 g) was dissolved inacetonitrile (10 ml), and the solution was brought to reflux temperaturewith vigorous stirring. The solution was subsequently cooled to 0° C.After a short period the clear solution was seeded with paroxetinemethanesulfonate seeds obtained in Example 26. A crystalline precipitateof paroxetine methanesulfonate acetonitrile solvate formed rapidly, andwas collected by filtration in an argon atmosphere, washed withacetonitrile and dried in a vacuum desiccator over phosphorouspentoxide.

[0180] Yield=4.1 g

[0181] Molar ratio of paroxetine to methanesulfonic acid=1:1

[0182] Acetonitrile content (estimated by NMR) 9.4% wt/wt.

[0183] IR and X-ray powder diffraction patterns similar to thoseobtained in example 26.

EXAMPLE 31

[0184] A solution of unpurified paroxetine free base (162 g) in toluene(1.0 liter) was charged to a nitrogen purged reactor, stirred at 20.5°C., and the pale straw colored mixture seeded with crystals ofparoxetine methanesulfonate. A solution of methanesulfonic acid (50.0 g)in propan-2-ol (250 ml) was introduced in a fine stream with goodagitation over a period of 5 minutes, giving a reaction temperature of32.9° C. The mixture was cooled to 25° C. over 1.5 hours, during whichthe bulk of the product crystallised in a controlled manner. The mixturewas further cooled to 21° C., and the dense white crystalline productfiltered, and washed with propan-2-ol (250+100 ml) and dried asdescribed below.

[0185] The solvent-wet cake (262 g) was placed in a Pro-C-epTMini-Microwave-Processor equipped with a condenser, and purged withnitrogen. The chamber temperature was set to 25° C., the cake agitatedat 25 rpm, and microwave radiation was applied at 100 watts at 100 mbarpressure. The temperature of the product rose to 32° C., and solvent wascollected in the receiver at a steady rate. After 30 minutes the producttemperature had risen to 35° C. and solvent condensation had ceased,indicating that drying was complete. This was confirmed by theapplication of full vacuum to the system, which resulted in no drop inthe temperature of the product. A total of 72 g of solvent wascollected.

[0186] Analysis of the white crystalline product by NMR showed that theresidual propan-2-ol level was less than 0.1% wt/wt, and analysis byX-ray powder diffraction gave a diffractogram which was the same as thatfor Example 3. Analysis by HPLC showed that the product was very pure(99.45% PAR), with a very significant improvement in the impurityprofile over the free base used in the preparation of themethanesulfonate salt:

[0187] Impurity profile by PAR (peak area ratio). Paroxetine HPLC peakFree base methanesulfonate peak 1 0.03% 0.00% peak 2 0.07 0.00 peak 30.05 0.00 peak 4 0.02 0.01 peak 5 0.01 0.01 peak 6 0.18 0.17 peak 7 0.100.09 peak 8 0.11 0.12 peak 9 paroxetine 93.48 99.45 peak 10 0.07 0.04peak 11 0.01 0.00 peak 12 0.04 0.01 peak 13 0.04 0.04 peak 14 0.06 0.00peak 15 0.12 0.00 peak 16 0.03 0.01 peak 17 0.01 0.00 peak 18 0.11 0.01peak 19 0.03 0.02 peak 20 0.02 0.00 peak 21 0.01 0.00 peak 22 5.32 0.01peak 23 0.02 0.00 peak 24 0.02 0.00 peak 25 0.01 0.00 peak 26 0.01 0.00

EXAMPLE 32

[0188] Paroxetine methanesulfonate (4.72 g) was added to water (4 ml)with stirring and the mixture was heated to reflux temperature. Theresulting solution was cooled to 18° C. and after evaporation of somesolvent slowly crystallised to give an off-white precipitate. After 8days the precipitate was collected by filtration under an argonatmosphere and dried in a vacuum desiccator over phosphorous pentoxideto yield crystalline paroxetine methanesulfonate.

[0189] Yield=1.9 g

[0190] X-ray powder diffractogram consistent with Example 3

EXAMPLE 33

[0191] Paroxetine methanesulfonate (2.59 g) was added to a mixture ofacetonitrile (24 ml) and water (1 ml) and the mixture was heated toreflux temperature with stirring. On cooling the solution a whiteprecipitate formed, which was collected by filtration, washed withacetonitrile and dried in a desiccator over phosphorous pentoxide togive crystalline paroxetine methanesulfonate acetonitrile solvate.

[0192] Yield=1.5 g

[0193] Molar ratio of paroxetine to methane sulfonic acid=1:1

[0194] IR attenuated total reflection:

[0195] Bands at 2549, 1622, 1514, 1487, 1471, 1417, 1377, 1336, 1270,1207, 1180, 1160, 1142, 1098, 1077, 1040, 1027, 1011, 987, 921, 867,844, 830, 792, 774, 718, 670, 613, 579 cm⁻¹.

EXAMPLE 34

[0196] Paroxetine methanesulfonate (2.89 g) was added, with stirring, toacetonitrile containing 1% water (25 ml), and the mixture was heated toreflux temperature. The resulting solution was cooled to roomtemperature (18° C.) whereupon a white solid precipitated. Theprecipitate was collected by filtration, washed with acetonitrile anddried in a desiccator over phosphorous pentoxide to yield crystallineparoxetine methanesulfonate acetonitrile solvate.

[0197] Yield=2.1 g

[0198] Molar ratio of paroxetine to methane sulfonic acid=1:1

[0199] IR attenuated total reflection: Bands at 2548, 1623, 1513, 1487,1471, 1418, 1377, 1336, 1270, 1207, 1180, 1159, 1142, 1098, 1040, 1027,1011, 987, 921, 867, 845, 831, 791, 774, 718, 670, 613 cm⁻¹.

EXAMPLE 35

[0200] Paroxetine base (11.74 g), which had been obtained from thehydrolysis of the phenyl carbamate precursor, was stirred inethylacetate (50 ml) and the mixture was gently heated to ensure totaldissolution. The hot solution was cooled to 35° C., then methanesulfonicacid (2.3 ml) was added dropwise. The solution was cooled, extractedwith water (3×70 ml), and the aqueous extracts combined. Most of thewater was removed by evaporation under reduced pressure, then toluenewas added and the evaporation repeated to remove residual water as anazeotrope. The oily residue was dissolved in propan-2-ol (20 ml), heatedto reflux temperature to dissolve, then cooled to give a whiteprecipitate. This precipitate was collected by filtration, washed withpropan-2-ol and dried in a vacuum desiccator over phosphorus pentoxideto yield crystalline paroxetine methanesulfonate.

[0201] Yield=10.3 g

EXAMPLE 36

[0202] A round bottomed flask was charged with a solution of paroxetinebase (8.6 g) in toluene (100 ml), which had been obtained from thehydrolysis of the phenyl carbamate precursor, and methanesulfonic acid(1.86 ml) was added dropwise. The resulting clear solution was placedinto a separating funnel, and extracted with water (3×100 ml). Theaqueous extracts were combined and evaporated under reduced pressure,then toluene was added and the evaporation repeated to remove residualwater as an azeotrope, to produce a crisp solid. The solid was dissolvedin toluene (60 ml) by heating to 70° C. and maintained at thattemperature. After 3 hours the precipitate that had formed was collectedby filtration under an atmosphere of nitrogen, washed with toluene anddried in a vacuum desiccator over phosphorus pentoxide to yieldcrystalline paroxetine methanesulfonate.

[0203] Yield 7. 1 g

EXAMPLE 37

[0204] A mixture of the N-benzyl derivative of paroxetinemethanesulfonate (3.0 g), 10% palladium on carbon catalyst (150 mg) andpropan-2-ol (60 ml) was stirred under an atmosphere of hydrogen(pressure 1 atm) at 60° C. for 5.5 hours. The warm mixture was filteredthrough celite and the filter cake washed with propan-2-ol (30 ml). Thevolume of the filtrate was reduced to 20 ml by evaporation under reducedpressure and the solution was stirred at 21 ° C. under a nitrogenatmosphere for 1 hour. A white crystalline product formed and wascollected by filtration, washed with cold propan-2-ol (2×5 ml) and driedat 40° C. under vacuum for 2 hours to give paroxetine methanesulfonate,1.85 g (75%).

EXAMPLE 38

[0205] Methanesulfonic acid (2.5 ml) in propan-2-ol (30 ml) was addeddropwise to a stirred solution of paroxetine acetate (13.6 g) inpropan-2-ol (130 ml) at 50° C. The solution was cooled to 40° C., seededwith crystalline paroxetine methanesulfonate, sonicated and stirred forone hour while the product crystallised. The resulting solid wascollected by filtration, washed with propan-2-ol (50 ml). and dried overphosphorus pentoxide in a vacuum desiccator to give crystallineparoxetine methanesulfonate as a crystalline white solid.

[0206] Yield=15.1 g

EXAMPLE 39

[0207] Paroxetine maleate form B (1.89 g) was dissolved in warmpropan-2-ol (50 ml) and a solution of methanesulfonic acid (0.29 ml) inpropan-2-ol (10 ml) was added. The solution was brought to refluxtemperature, cooled to 30° C., seeded with crystalline paroxetinemethanesulfonate and sonicated. Crystallisation rapidly occurred. Thethick suspension was diluted with propan-2-ol (20 ml), and theprecipitate was collected by filtration, washed with propan-2-ol (30 ml)and dried over phosphorus pentoxide in a vacuum desiccator to yieldcrystalline paroxetine methanesulfonate.

[0208] Yield=1.4 g

EXAMPLE 40

[0209] Methanesulfonic acid (0.4 ml) in propan-2-ol (10 ml) was addeddropwise to a stirred solution of paroxetine maleate form A (2.95 g) inpropan-2-ol (40 ml). The reaction was brought to reflux temperature,cooled to 30° C., seeded with crystalline paroxetine methanesulfonate,and sonicated.

[0210] Crystallisation rapidly occurred. The crystals of paroxetinemethanesulfonate were collected by filtration, washed with propan-2-ol(40 ml) and dried over phosphorus pentoxide in a vacuum desiccator.

[0211] Yield=2.1 g

EXAMPLE 41

[0212] Paroxetine L(+) tartrate (18.5 g) was added to propan-2-ol (150ml) and water (20 ml) and the mixture was brought to reflux temperaturewith stirring to ensure total dissolution. The solution was cooled to50° C. and methanesulfonic acid (2.8 ml) in propan-2-ol (10 ml) wasadded. Propan-2-ol (60 ml) was added and solvent (170 ml) was removed bydistillation. The clear yellow solution was seeded with crystallineparoxetine methanesulfonate, sonicated, cooled to 0-5° C. and a whiteprecipitate formed. The solid was collected by filtration, washed withpropan-2-ol (40 ml) and dried to yield crystalline paroxetinemethanesulfonate.

[0213] Yield=4.4 g

EXAMPLE 42

[0214] Methanesulfonic acid (0.6 ml) in propan-2-ol (25 ml) was addeddropwise to a stirred solution of paroxetine L(+) tartrate (4.99 g) inwater (25 ml) at 50° C. After 1 hour, the solvents were removed atreduced pressure to afford a crisp solid. Propan-2-ol (25 ml) was addedand the mixture was heated to reflux temperature, seeded withcrystalline paroxetine methanesulfonate and cooled to 0-5° C. to afforda white precipitate. The precipitate was collected by filtration, washedwith propan-2-ol (30 ml) and dried in a vacuum desiccator to givecrystalline paroxetine methanesulfonate.

[0215] Yield=1.9 g

EXAMPLE 43

[0216] A round bottom flask was charged with unpurified paroxetine base(8.6 g) in toluene (20 ml) which had been prepared by potassiumhydroxide hydrolysis of a phenylcarbarnate derivative, and a solution ofmethanesulfonic acid (1.9 ml) in toluene (10 ml) was added dropwise. Theresulting clear solution was placed into a separating funnel andextracted with water (30 ml). The aqueous phase was separated, residualtoluene removed by evaporation at reduced pressure and the remainingclear solution (25 ml) was further diluted with water (40 ml). The waterwas removed by freeze drying to afford amorphous paroxetinemethanesulfonate.

[0217] Yield=9.1 g

[0218] Infra-red (attenuated total reflection) Bands at: 1605, 1510,1503, 1488, 1470, 1394, 1335, 1269, 1219, 1178, 1158, 1098, 1034, 928,831, 799, 773, 653, 612, 593, 579, 569 cm⁻¹.

EXAMPLE 44

[0219] Methanesulfonic acid (1.86 ml) in toluene (15 ml) was addeddropwise to a stirred solution of unpurified paroxetine base (8.6 g) intoluene (20 ml) which had been prepared by potassium hydroxidehydrolysis of a phenylcarbamate derivative. The clear solution wasplaced into a separating funnel and extracted with water (15 ml). Theaqueous phase was separated and the water removed by evaporation atreduced pressure. Propan-2-ol (50 ml) was added, and residual water wasremoved by evaporation at reduced pressure as an azeotrope withpropan-2-ol. The remaining solution (40 ml) was heated to 40° C. andstirred while the product crystallised. The resulting paroxetinemethanesulfonate was collected by filtration, washed with propan-2-ol(20 ml) and dried over phosphorus pentoxide in a vacuum desiccator.

[0220] Yield=9.1 g

EXAMPLE 45

[0221] Methanesulfonic acid (2.1 ml) in propan-2-ol (10 ml) was addeddropwise to a stirred solution of paroxetine base (11.92 g) inpropan-2-ol (30 ml). The resulting clear solution was heated to 50° C.and hexane (200 ml) containing seed crystals of paroxetinemethanesulfonate was added in small volumes. The solution was vigorouslystirred at approximately 50° C. for 30 minutes to crystallise. Theresulting white solid was collected by filtration, washed with hexane(50 ml) and dried in a vacuum desiccator over phosphorus pentoxide toproduce crystalline paroxetine methanesulfonate

[0222] Yield 13.02 g

EXAMPLE 46

[0223] To a stirred solution of paroxetine base (20.9 g) in propan-2-ol(70 ml) was added methanesulfonic acid (3.7 ml) in propan-2-ol (10 ml).The solution was heated to 50° C. and added portion-wise to hexane (200ml) also at 50° C. The solution was stirred vigorously to form aprecipitate which was stirred further to ensure crystallisation. Theprecipitate was collected by filtration, washed with hexane (40 ml) anddried in a vacuum desiccator over phosphorus pentoxide to giveparoxetine methanesulfonate as a white crystalline solid.

[0224] Yield=23.1 g

EXAMPLE 47

[0225] Amberlite ‘IRA’-93(OH) (78 g) was slurried in water and pouredinto a column (10 cm×4.5 cm). The eluting solvent was gradually changedfrom water to methanol, and the column was repacked. The resin wasconverted to the methanesulfonate form by eluting with methanesulfonicacid (2.2 ml) in methanol (50 ml), and excess acid was washed off thecolumn with methanol (300 ml). A solution of paroxetine hydrochloride(6.9 g) in methanol (50 ml) was loaded onto the column and elutedthrough with methanol (350 ml) over I hour. The methanol eluent wasevaporated at reduced pressure to an oil. Propan-2-ol (100 ml) was addedand the mixture was heated to 60° C., seeded with crystalline paroxetinemethanesulfonate and cooled to room temperature (18° C.). The resultingwhite precipitate was collected by filtration, washed with propan-2-ol(20 ml) and dried in a vacuum desiccator over phosphorus pentoxide togive paroxetine methanesulfonate as a white crystalline solid.

[0226] Yield=6.6 g

EXAMPLE 48

[0227] Amberlite IRA-93 (OH) resin (basic form) (146 g) was slurried inwater and poured into a column (16.5 cm×4.5 cm). The eluting solvent wasgradually changed from water to water/methanol (1:1) and the column wasrepacked. The resin was converted to the methanesulfonate form byeluting with methanesulfonic acid (10 ml) in methanol/water (1:1) (20ml), and excess acid was washed off the column with methanol/water (1:1)(350 ml). A solution of paroxetine hydrochloride (12.86 g) inmethanol/water (1:1) (50 ml) was loaded onto the column and eluted withmethanol:water (1:1) (350 ml) over 1 hour. The eluent was evaporated atreduced pressure to give a crisp solid. Propan-2-ol (120 ml) was addedand the mixture was heated to reflux temperature and cooled to 40° C.The resulting white precipitate was collected by filtration, washed withpropan-2-ol (50 ml) and dried in a vacuum desiccator over phosphoruspentoxide to give paroxetine methanesulfonate as a white crystallinesolid.

[0228] Yield=14.8 g

EXAMPLE 49

[0229] Methanesulfonic acid (1.00 ml) was added to a solution of(3S,4R)-3-(Benzo[1,3]dioxol-5-yloxymethyl)-4-(4-fluoro-phenyl)piperidine-1-carboxylicacid tertbutyl ester (3.30 g) in propan-2-ol. The reaction mixture wasstirred at 22° C. under nitrogen for 4 hours then the reaction mixturewas concentrated to approximately 20 ml, seeds of paroxetinemethanesulfonate salt added (approximately 20 mg) and the solution leftto crystallise. After standing for 19 hours at 22-23° C., needlecrystals of paroxetine methanesulfonate were collected by filtration,washed with propan-2-ol and dried under vacuum. A second crop ofparoxetine methanesulfonate was collected from the filtrate afterstanding at 23° C. for 6 hours.

EXAMPLE 50

[0230] A solution of(Benzo[1,3]dioxol-5-yloxymethyl)-4-(4-fluorophenyl)piperidine-1-carboxylicacid tert-butyl ester (4.10 g) in dichloromethane was treated with asolution of methanesulfonic acid (0.97 g) in dioxane (20 ml) at 22° C.The reaction mixture was stirred at this temperature for 48 hours, thenmethanesulfonic acid (1 ml) was added and the reaction mixture heated atreflux for 5 hours. The mixture was cooled to room temperature (22° C.)and left to stand for for 22 hours, then evaporated to approximately 10ml under reduced pressure. Propan-2-ol was added (60 ml) and thesolution seeded with paroxetine methanesulfonate (20 mg) and stirred atroom temperature for 1 hour. Paroxetine methane sulfonate was isolatedby filtration, washed with cold propan-2-ol (5 ml) and dried undervacuum. Yield 2.38 g.

EXAMPLE 51

[0231] Aqueous hydrochloric acid (0.48M, 25.0 ml) was added to a stirredsolution of paroxetine methanesulfonate (5.0 g) in water (50 ml) at 40°C. over a period of 15 minutes. The resulting thick white suspension wasstirred and cooled to 20° C. The product was collected by filtration,washed with water (20 ml) and dried at 40° C. under vacuum overphosphorus pentoxide for 2 hours to give crystalline paroxetinehydrochloride hemihydrate, 3.9 g. The infra-red spectrum obtained wasconsistent with that of crystalline paroxetine hydrochloridehemihydrate.

EXAMPLE 52

[0232] Paroxetine methanesulfonate was added portionwise over a periodof 5 minutes to dilute aqueous hydrochloric acid (0.172M, 75 ml) at 21°C. A precipitate formed quickly, but the mixture was stirred for 30minutes to ensure complete crystallisation. The product was collected byfiltration washed with water (20 ml) and dried at 40° C. under vacuumover phosphorus pentoxide for 2 hours to give crystalline paroxetinehydrochloride hemihydrate, 4.0 g. The infra-red spectrum obtained wasconsistent with that obtained for crystalline paroxetine hydrochloridehemihydrate.

EXAMPLE 53

[0233] A solution of paroxetine methanesulfonate (5.0 g) in water (20ml) was added to dilute hydrochloric acid (0.10M, 125 ml) at 40° C. withstirring over a period of 10 minutes. The resulting suspension wasstirred and cooled to 20° C. and the product was collected byfiltration. The filter cake was washed with water (30 ml) and theproduct dried at 40° C. under vacuum over phosphorus pentoxide for 2hours to give crystalline paroxetine hydrochloride hemihydrate, 3.1 g.The infra-red spectrum obtained was consistent with that obtained forcrystalline paroxetine hydrochloride hemihydrate.

EXAMPLE 54

[0234] INGREDIENTS 20 mg Tablet 30 mg Tablet Paroxetine Methanesulfonate20.00 mg 30.0 mg (calc. as free base) (calc. as free base) DicalciumPhosphate (DCP) 83.34 mg 125.0 mg Microcrystalline Cellulose 50.67 mg76.0 mg Sodium Starch Glycollate 8.34 mg 12.5 mg Magnesium Stearate 1.67mg 2.5 mg

[0235] Commercial Source of the Ingredients

[0236] Dicalcium Phosphate Dihydrate—Emcompress or Ditab*

[0237] Microcrystalline Cellulose—Avicel PH 102*

[0238] Sodium Starch Glycollate—Explotab.*

[0239] * Trade Names

[0240] Method

[0241] 1. Pass DCP through a screen and weigh it into a Planetary mixer.

[0242] 2. Add 30 mesh Paroxetine Methanesulfonate to the bowl.

[0243] 3. Add 20 mesh Avicel and Explotab and mix all the powders for 10minutes.

[0244] 4. Add magnesium stearate and mix for 5 minutes.

[0245] Tablet into Pentagonal Tablets using the Following Punches 30 mgTablet  9.5 mm Circumcircle 20 mg Tablet 8.25 mm Circumcircle

[0246] The tablets are made satisfactorily on a single punch or a Rotarypress.

EXAMPLE 55

[0247] INGREDIENTS 10 mg Tablet 20 mg Tablet 30 mg Tablet Paroxetine 10mg 20 mg 30 mg Methanesulfonate (calc as free base) (calc as free (calcas free base) base) Sodium Starch Glycollate 2.98 mg 5.95 mg 8.93 mgGranular Dicalcium 158.88 mg 317.75 mg 476.63 mg Phosphate (DITAB) orDicafos Magnesium Stearate 1.75 mg 3.50 mg 5.25 mg

[0248] Method

[0249] 1. Paroxetine Methanesulfonate, Sodium Starch Glycollate andDicalcium Phosphate Dihydrate are screened and mixed together in asuitable mixer. (Planetary, Cuble or High Energy Shear mixer.)

[0250] 2. Add Magnesium Stearate and compress it into a tablet using asingle punch or Rotary Tablet machine.

1. Paroxetine methanesulfonate.
 2. A compound according to claim 1 innon-crystalline form.
 3. A compound according to claim 1 in crystallineform.
 4. A compound according to claim 3 having inter alia the followingcharacteristic IR peaks: 1603, 1513, 1194, 1045, 946, 830, 776, 601,554, and 539±4 cm−1.; and/or the following characteristic XRD peaks:8.3, 10.5, 15.6, 16.3, 17.7, 18.2, 19.8, 20.4, 21.5, 22.0, 22.4, 23.8,24.4, 25.0, 25.3, 25.8, 26.6, 30.0, 30.2, and 31.6±0.2 degrees 2 theta.5. A process for the preparation of a compound as claimed in claim 1 or2 by precipitation from a solution of a paroxetine methanesulfonate,spray drying or freeze drying a solution of a paroxetinemethanesulfonate, evaporating a solution of a paroxetinemethanesulfonate to a glass, or by vacuum drying of oils of a paroxetinemethanesulfonate, or solidification of melts of a paroxetinemethanesulfonate.
 6. A process for the preparation of a compound asclaimed in claim 3 or 4 by crystallization or re-crystallization from asolution of a paroxetine methanesulfonate in a solvent.
 7. A processaccording to claim 5 or 6 in which the solution, oil or melt of aparoxetine methanesulfonate is prepared by chemical modification of aprecursor paroxetine methanesulfonate salt.
 8. A process according toclaim 5 or 6 in which the solution, oil or melt of a paroxetinemethanesutfonate is prepared by treating paroxetine free base or alabile derivative thereof with methanesulfonic acid or a labilederivative thereof.
 9. A process according to claim 8 in which theparoxetine free base or a labile derivative thereof is provided in situfrom a preceding reaction step in which the paroxetine free base, or alabile derivative thereof, has been formed.
 10. A process according toclaim 8 or 9 in which the labile derivative of paroxetine free base isan organic acid salt thereof and the labile derivative ofmethanesulfonic acid is an ammonium or amine salt thereof.
 11. A processaccording to claim 5 or 6 in which the solution, oil or melt of aparoxetine methanesulfonate is prepared by deprotecting an acid-labileprotected paroxetine precursor with methanesulfonic acid.
 12. A processaccording to any one of claims 6 to 11 in which the solvent comprises anaromatic hydrocarbon, water, an alcohol, an ester. a ketone, an amide, aheterocyclic amine, a halogenated hydrocarbon, a nitrile, an ether or amixture thereof.
 13. A process according to claim 12 in which thesolvent comprises toluene an alcohol, an ester, a ketone, a halogenatedhydrocarbon, a nitrile, or an ether, optionally in admixture with water,an ether, or a lower alcohol, or mixtures thereof.
 14. A processaccording to any one of claims 6 to 13 in which the solvent forms anazeotrope with water and prior to isolation of the product water isremoved by azeotropic distillation.
 15. A process according to any oneof claims 6 to 14 in which the crystallisation is promoted by inclusionof an anti-solvent to the solvent.
 16. A process according to claim 15in which the anti-solvent is an ether or hexane.
 17. A process accordingto any one of claims 6 to 16 in which the cryvstallisation is conductedat elevated temperature followed by controlled cooling.
 18. A processaccording to any one of claims 6 to 17 in which crystallisation isinduced by the addition of a seed crystal.
 19. A process according toany one of claims 6 to 17 in which crystallisation is conducted withoutthe addition of a seed crystal.
 20. A pharmaceutical compositioncomprising a compound according to any one of claims 1 to 4 and apharmaceutically acceptable carrier.
 21. A composition according toclaim 20 in which the carrier comprises a disintegrant.
 22. Acomposition according to claim 20 or 21 in which the carrier comprises abinder.
 23. A composition according to any one of claims 20 to 22 inwhich the carrier comprises a coloring agent.
 24. A compositionaccording to any one of claims 20 to 23 in which the carrier comprises aflavouring agent.
 25. A composition according to any one of claims 20 to24 in which the carrier comprises a preservative.
 26. A compositionaccording to any one of claims 20 to 25 adapted for oral administration.27. A composition according to claim 26 which is a tablet or capsule.28. A composition according to claim 27 which is a modified oval shapedtablet.
 29. A composition according to any one of claims 20 to 28comprising 1 to 200 mg of active ingredient, calculated on a free basebasis.
 30. Use of a compound according to any one of claims 1 to 4 inthe manufacture of a medicament for use in the treatment and/orprevention of any one or more of the Disorders.
 31. A method fortreating and/or preventing any one or more of the Disorders byadministering an effective and/or prophylactic amount of a compoundaccording to any one of claims 1 to 4 to a sufferer in need thereof. 32.A 1:1 solvate of paroxetine methanesulfonate with acetonitrile.
 33. Useof paroxetine methanesulfonate as an intermediate in the preparation ofthe hydrochloride.
 34. A process for preparing paroxetine hydrochlorideby converting paroxetine methanesulfonate.
 35. A pack containing apharmaceutical composition according to any one of claims 20 to
 29. 36.A compound according to claim 3 substantially as hereinbefore describedin Example
 2. 37. A compound according to claim 3 or 32 substantially ashereinbefore described in any one of Examples 3 to
 50. 38. A processaccording to claim 34 substantially as hereinbefore described in any oneof Examples 51 to
 53. 39. A composition according to claim 20substantially as hereinbefore described in Example 54 or 55.